Method of inducing antiandrogenic activity



United States Patent Int. Cl. A 61k 17/06 US. Cl. 424-241 2 Claims ABSTRACT OF THE DISCLOSURE Method of inducing antiandrogenic activity in mammals by administering an effective amount of 10,11-lactone of 17a-ethynylA -estrene-1 15,175-diol-3-one105- carboxylic acid of the formula CH OH PRIOR ART Numerous compounds having antiandrogenic properties are known but most of the known compounds have the disadvantage of also possessing endocrinic activities among other activities. For example, progesterone or 6- chloro 6 dehydro 17a hydroxy progesterone possess obviously progestative properties, estradiol derivatives have an estrogenic activity and A-nor-testosterone and 17-methyl-B-nor testosterone possess androgenic activity. Other antiandrogenes, such as testololactones possess antiandrogenic activity when administered in small doses, but this acitvity is reversed at increased doses. 10,11 lactone of 17a ethynyl A estrene 115,175- diol-3-one-105-carboxylic acid has the two-fold advantage of not possessing parasitic endocrinic activity, such as androgenic activity, estrogenic activity or progestomimetic activity while having a constant antiandrogenic activity in proportion to the dose administered. The said product has the further advantage of being active when administered orally which greatly facilitates administration.

OBJECTS OF THE INVENTION It is an object of the invention to provide novel antiandrogenic compositions which do not possess other undesired activities.

It is another object of the invention to provide a novel method of treating hyperandrogenia in mammals.

It is a further object of the invention to provide a novel process for the preparation of 10,11-lactone of 170: ethynyl A estrene 115,175 diol 3 one 105- carboxylic acid.

These and other objects and advantages of the invention Will become obvious from the following detailed description.

THE INVENTION The novel antiandrogenic compositions of the invention are comprised of 10,11-lactone of 17a-ethynyl-A -estrene- 1l5,175-diol-3-one-105-carboxylic acid and a major amount of a pharmaceutical carrier. The compositions may be in the form of injectable solutions or suspensions, put up in ampoules or multiple-dose flacons, in the form of tablets, coated tablets, sublingual tablets and suppositories prepared in the usual manner. The compositions 3,458,632 Patented July 29, 1969 preferably contain 10 to 25% by weight of the lactone or to 500 mg. per dose.

The novel method of the invention for the treatment of hyperandrogenia in mammals comprises administering to mammals an efiective amount of 10,11-lactone of 170:- ethynyl A estrene 115,175 diol 3 one carboxylic acid. The said lactone may be administered orally, perlingually, transcutaneously or rectally. The usual useful dosage is 1.45 to 7.25 mg./kg. per individual dose and 2.9 to 14.5 mg./kg. per day for the adult depending upon the method of administration.

The novel process of the invention for the preparation of 10,11-lactone of 17u-ethynyl-A -estrene-115,175-diol- 3-one-105-carboxylic acid comprises oxidizing 10,11-lactone of 3 ethylenedioxy A estrene 115,175 diol- 105-carboxylic acid to form 10,11-lactone of 3-ethylenedioxy A estrene o1 17 one 105 carboxylic acid, reacting the latter with an ethynylation agent to form 10,11-lactone of 3-ethylenedioxy-17m-ethynyl-A estrene-115,175-diol-105-carboxylic acid and hydrolyzing the latter under acidic conditions to form 10,11-lactone of 17a ethynyl A estrene 115,175 diol 3 one- 105-carboxy1ic acid. The reaction scheme is illustrated in Table I.

TABLE I O OH O l OH sYCI QEOH 3 ingly, the lactone group is not affected by the Grignard reagents.

The acid hydrolysis of 10,11-lactone of 3-ethylene-dioxy-l7a-ethynyl-A -estrene-l1,6,17,8-diol 105 carboxylic acid may be etfected in an aqueous protonic solvent, such as aqueous acetic acid or an aqueous lower alkanol such as aqueous methanol or ethanol in the presence of a strong acid such as perchloric acid, hydrochloric acid, sulfuric acid, p-toluene-sulfonic acid, etc.

In the following example, there are described several theory) of l0,ll-lactone of 3-ethylenedioxy-17a-ethynyl- A -estrene-1113,l7fl-diol-10B-carboxylic acid having a melting point of 270 C. and a specific rotation of (c.=0.5% in tetrahydrofuran.)

The product was white and was insoluble in water and dilute acids, soluble in hot alcohol and hot acetone, and soluble in cold chloroform.

Analysis.C H O molecular weight: 384.45. Calcu- 10 preferred embodiments to illustrate the invention. Howg? 3' 1 E 1? 1 ever, it should be understood that the invention is not inep i .g a tended to be limited to the specific embodiments. estrene' fi' oxy 1c 0 10,11-lactone of 3-ethylened1oxy-l7a-ethynyl-A -estrene- Example I.Prepa 0f 10.11-1aCt0I1e 0f y y 1113,l7/3-di0l-l0fl-carboxylic acid were introduced into 70 A4-eStIe11e-1 fi fi' fiy acid cc. of acetic acid containing 10% perchloric acid (at 55 Step Preparation of lolblactone of 3 ethy1ene B). The reaction mixture was agitated for 2 hours under OX3 Aiestrenedl ficarboxflk an atmosphere of nitrogen at room temperature and then of chromic acid were Suspended in 32 of pyridine 350 cc. of methylene chloride and 150 cc. of water were cooled to about 0 C. and the suspension was agitated for 20 added to the reijlctlon F f The F P mlxture was A hour. Then a solution of 3.2 g. of 10,1l-lactone of 3- then made alkahne by i of sodlum ethylenedioxy-A -estrene-115,17 3-di0l-IOfl-carboxylic acid canted Washed dned' The Product was (118801? (prepared by the process of Patent No. 3,150,127), dis- Wi chlonde 9hromatographed through m?g,ne5mm Solved in 32 of redistmed pyridine was slowly added silicate and eluted w th methylene chlorlde containing 2% to the Suspension of acetone, to obtain 290 mg. of 10,11-lactone of 17ath n l-A -estrene-l1/8,17/3-d1ol-3-one-l0/3-carboxyl1c acid The reaction mixture was agitated for 16 hours at room g X y o temperature, and after 3.2 cc. of methanol Were added, havmg zomeltm'g i 232 i speclfic rotatlon the agitation was continued for another 15 minutes. Then of [ab methemflx the reaction mixture was extracted with methylene chlo- Product f and was msqlubk m water and ride and the extract was washed with Water dried and dilute aqueous acids, slightly soluble in hot alcohol and subjected to chromatography through magnesium silicate acetone a Soluble m cold chloroform and eluted with methylene chloride containing 3% of AMIYWS'TTCZIHMOQ molecular welght=34o'4' Calcu' pyridine to obtain 3.092 g. of product, which was utilized J Med: 74'09 Found: 740%; as such for the next step of the synthesis. PHARMACOLOGICAL DATA For the P p of analysis, the li'wdllet Obtained Was 35 The antiandrogenic activity was determined on castriturated in methyl aleohol-isopfopyl ether mixture (114, trated male rats according to the Lerner method described vacuum filtered, washed and dried to obtain 10,11-lactone b Dorf i Methods i Hormones Research, 11 0f y yfifipage 320. Male rats, about 4 weeks old, were castrated 6 acid, having a melting Point Of and a Specific and treatment started on the day after the castration and ot 0f ]n in methaIlOD- 40 lasted 7 days. On the 8th day, the animals were sacri- Ana ysi z1 26 5; molecular Weight-135842- Calellficed, and the following organs were removed and latedi Found: 700%; weighed: prostate gland, seminal vesicles and levator ani.

p B. Preparation of 10-11 lactone of 3-ethylenedi- The 10,11-lactone of 17a-ethynyl-A -estrene-1113,17fi-diol- Y- y B 5' 1 earboxylie 3-one-10 3-carboxylic acid, (product A), was administered acid.--3 g. of magnesium were introduced into 165 cc. of orally at doses of 1 and 5 mg. per rat per day, as a susanhydfous tetrahydrofuran, and me hyl b de was pension in a dispersive aqueous liquid, simultaneously allowed to bubble through the reaction mixture until the with 507 of testosterone propionate per rate per day, magnesium had completely disappeared. Then the current administered subcutaneously, as a solution in olive oil of methyl bromide was replaced by a current of acetylene admixed with 5% benzyl alcohol. The groups of rats which current was allowed to bubble through the reaction tr at d wer arranged s follo mixture for 3 hours while maintaining a temperature of (1) One group of control animals received the disabout 35 C. Thereafter, the reaction solution was cooled persive aqueous liquid; and decanted. 2.9 g. of 10,11-lactone of 3-ethylenedioxy- (2) One group of rats received 507 of testosterone A -estrene-llfi-ol-l7-one-l0fi-carboxylic acid were intropropionate administered subcutaneously; duced into 160 cc. of the said reaction solution and the (3) One group of rats received 1 mg. of product A mixture was refluxed for 2 hours, then cooled and poured by oral administration; into an aqueous solution of ammonium chloride. The re- (4) One group of rats received 5 mg. of product A action mixture was then extracted with methylene chloride by oral administration; and the extract was washed with water, dried and purified (5) One group of rats received 1 mg. of product A by passing it through a column of magnesium silicate to by oral administration and 507 of testosterone propionate obtain 3.042 g. of 10,11-lactone of 3-ethylenedioxy-17otby subcutaneous administration; ethynyl-A -estrene-1113,17,6-diol-10fl-carboxylic acid. (6) One group of rats received 5 mg. of product A by For analysis, the said product was triturated in a methyl oral administration and 50 of testosterone propionate by alcohol-isopropyl ether mixture (1:4), then vacuum filsubcutaneous administration. The results are summarized tered and washed to obtain 2.591 g., (a yield of 83% of in Table II.

TABLE II Fresh Levator Dry Levator A111 in g. per .Ani in g. per Seminal Ventral Treatment 1000 g. of Bet 1000 g. of rat Vesicles mg. Prostate mg.

Control '0. 239 0. 049 4. 4 10. 9 50 of testosterone proplonate 0. 467 0. 097 87. 0 95. 3 1 mg. of Product A 0. 241 0. 054 8.6 11. 5 5 mg. of Product A 0. 255 0. 052 11. 7 1g, 2 1 mg. of Product A and 50 of testesterone propionate 0. 460 (2%) 0. 094 (3%) 71.0 (18%) 100.5 (+595) 5 mg. of Product A and 507 of testosterone propionate 0.363 (22%) 0.078 (-20%) 44.9 (48%) 71.6 (-25%) 5 Table II establishes that 10,11-lactone of Nix-ethynyl- -estrene-11,8,17fi-di01-3-0ne-1OB-carboxylic acid exerts a distinct antiandrogenic and antianabolic activity at a dose of 5 mg. when administered with testosterone propionate and when administered alone, it has practically no anabolic and androgenic effect.

Various modifications of the compositions and meth- 0d of the invention may be made without departing from the spirit or scope thereof.

We claim:

1. A method of inducing antiandrogenic activity in mammals which comprises administering to mammals an antiandrogenically effective amount of 10,11-lactone of 170a ethynyl A estrene 115,175 diol 3 onelOtd-carboxylic acid.

2. The method of claim 1 wherein the amount of the 10,11-lactone administered is 2.9 to 14.5 mg./kg. per day.

References Cited UN TED STATES PATENTS 3,167,548 1/1965 Cross 260'239.57

FRANK CACCIAPAGLIA, IR., Primary Examiner 

